Our understanding of the physiology of the tubercle bacillus is limited by our artificial in vitro axenic growth conditions. The completion of the genomic DNA sequence of a virulent strain of the bacterium (H37Rv) offered a glimpse into the varied metabolic potential of this complex Actinomycete. Far from the textbook description of an obligate aerobe, the tubercle bacillus has preserved all of the machinery necessary for life without oxygen. Likewise, far from growth on glucose in a laboratory flask the bacillus appears to be supremely adapted for living off of abundant host lipid constituents. The studies encompassed within this project all have in common the aim of discerning the nature of the intracellular physiology of Mycobacterium tuberculosis and modulation of the host's response to infection during actual disease. These studies have been informed and facilitated by the availability of the genome sequence. *We have used this information to predict the regulatory pathways involved in bacterial latency including the use of a small hyperphosphorylated nucleotide that coordinates entry of the bacteria into stationary phase. We have demonstrated that disabling this regulatory network eliminates the organisms' ability to enter dormancy and interferes with long-term survival. *The suggestion from the genome that potent immunoregulatory molecules called polyketides were produced led us to explore the immunomodulatory effects of various mycobacterial lipidic fractions from recent patient isolates in collaboration with a group at Rockefeller University. These studies have shown significant variation amongst clinical isolates of TB that have important ramifications for infected patients. *The genome sequence suggested that DNA repair enzymes in TB were unusual compared to other prokaryotes. Section scientists have utilized this information to dissect the mechanisms of mutation and repair in the bacterium and demonstrate that these sstems are critical to the long-term survival of the organism.